Document kBJke43DXY0Y7QRZj6ZyBbVD

Mortality Experience of Workers in a Vmyl Chloride Monomer: Production Plant Patricia A. Buffler, Ph.D.; Susan Wood, M.A.; Clayton Eifler, Ph.D.; Lucina Suarez, M.S.; and Duane J. Kilian, M.D. The evidence associating exposure to vinyl chloride with the rlsk~of tumors of various sites, including lung cancer, is inconsistent. In 7976 a mortality follow-up study of 464 white males employed in a vinyl chloride monomer (VCM) production plant since 1948 was conducted. Vital status was ascertained for 100% of the cohort. Eight (28.5%) of the 28 deaths observed were due to malignant neoplasms. No angiosarcomas or other liver tumors were observed. A statistically significant excess was noted for malignant neoplasms of the respiratory system (p=.03). The effect of smoking, duration of exposure to VCM, level of exposure, and the combined effect of duration and level of exposure were analyzed separately. A five-year latency requirement was maintained for all analyses except for the smoking analysis. Levels of exposure to VCM prior to 1971 were estimated from monitoring data available for the period 1971-75 by extrapolating the relative levels for job classifications backwards in time. Smoking histories were not available for 27.6% of the cohort. When it was as sumed that all "unknowns"smoked, a significant excess o* respiratory cancer was still observed (p=.05) When the minimum latency period of five years restricted analysis to the mortality experience after five years from date of initial exposure to VCM for the 314 employees satisfying this cri terion, the excess of respiratory cancer was moderate but not significant (p =.06). Both a longer duration and a higher level of exposure during the first five years following the date of initial exposure were associated with a statistically significant excess of respiratory cancer (p=.02 and p=.03, respectively). However, when duration and level of exposure were combined in an overall exposure index, the results were not significant (p = .07) The discrepancy in the results from the dose-response analyses may be due to the From th#1 Unuerstty of Texas School of Public Health, PO. Box 2016b. Houston, TX 77025 (Dr. Buffler and Ms Wood and Suarez). Department of Preventive Medicine and Community Health, Umvers tv of Texas Medical Branch. Caheston, TX 77S50 (Dr Eifler), and Occupational Health and Medical Research. Dow Chemical Company, Freeport, TX 77541 fDr Kihan) Journal ol Occupational Medicine/Vol. 21, No. 3/March 1979 potential error in the estimated levels and the small number of events observed, but the results do suggest that a je!liQrhiQ_xj2)2_j2gtween exposure to VCM_and respiratory cancer. I he association of vinyl chloride and the develop ment of angiosarcoma of the liver has been well documented. Vinyl chloride has also been described as a multi-system carcinogen causing tumors in the lung, cen tral nervous system, and hematopoietic systems.1'4. Most recently it has been suggested that vinyl chloride is a chemical mutagen and teratogen.' arl^jn1974, three cases of angios_arcoma of the liver, an extremely rare tumor, were reported among workeisjn a vinvl rhlnriflp polymerization plant.* All three workers had at one time been involved in the manual cleaning of polymerization reactors.7 In a recent report from Canada, this pattern was confirmed in 10 cases of angiosarcoma of the liver.* Seven of the workers cleaned reactors, and the rest were either operators or maintenance personnel. In itial exposures for all cases occurred before 1962. Following early reports, several epidemiologic studies of workers exposed to vinyl chloride were initiated. The first of these investigations was a proportionate mortality study by Monson and Peters.1. The study involved 161 deaths from two vinyl chloride plants: a plant producing vinyl chloride monomer (VCM), and the polymerization plant where the initial cases of angiosarcoma were iden tified. The deaths, which occurred between 1947 and 1974 among active and retired employees, were analyzed for excesses in cancer mortality. Monson and Peters reported a 50% excess in the proportion of deaths due to all malig nant neoplasms. Specific excesses were found for liver and biliary tract, lung and brain. These roo.lK ^ingested that vinvl rhl"'1,1" -"y carcinogen,. although the excesses reported were based on propor- EC- 1521 195 donate mortality ratios, which are not specifically a measure of risk. In 1974, Tabershaw and Gaffey1 published results of an industry-wide historical prospective study of 8,384 workers involved in the manufacture of vinyl chloride and vinyl chloride polymers in 33 plants. The study was restricted to individuals who had at least one year of ex posure to vinyl chloride before December 31, 1972. Ex cesses for. the specific causes of death were not statisti cally significant, except for cancer of the digestive system, consisting primarily of previously identified angiosarcomas of the liver. The excesses for cancers of the respiratory system and lymphomas, while not statistically significant, were suggestive of possible risks which appeared to be related to the dose of vinyl chloride. Dose was measured by an average monthly ex posure score determined for each worker and based on a subjective estimate of relative levels of exposure for jobs within each plant. The authors quite correctly point out that exposure levels between plants may not have been comparable. In addition, the inclusinn_nf many workers vuirh insrtppMTno iMflnry porinrU qc short as nnp year may have ohsciired-the evnosure effects This study had been extended to more adequately evaluate latency and to include more complete information regarding the study cohort.' The final report is therefore based upon a total group of 10,173 employees from 37 plants, of whom 9,677 (95.1 %) were successfully traced. While there were no statistically sipnifirant nf titP specific malignancies except-tor livpjr fanpinsarromat and brain. rho--iclr nf malipnant Jif thn rarfiirn.m^i.rfyrtru-r' doIgsabflSAr to be associated with intensity of exposure-- a standardized mortality ratio of 92 for the low intensity category compared to that of 141 for the high intensity category. In a study presented at the New York Academy of Science conference on vinyl chloride, Nicholson et al3 described an excess in total mortality and in overall cancer mortality among 257 men with five or more years of exposure occurring before 1963 in a polymerization plant. In addition, they reported three deaths due to an giosarcoma of the liver, one due to cancer of the brain, two due to lymphoma and none due to lung cancer. Two additional mortality studies10 " resulted in essenf-tially negative results. One of these, a mortality follow-up I study of 594 employees at the Dow fjhemiral rnmn^ny | polymer'plant in Midland Michigan, by Ott et al,10 re- I vealed excesses In overall cary-nr-nnlv in the high ex- / posure category (> 220 ppm). In this study, evaluation of I the effects of vinyl cnionde was confounded by the fact I pf coa employees had also been exposedja. / arsenic, a known carcinogen aneenng tne respiratory system. Analysis of the mortality experience among the cohort without the aresnic exposed workers indicated a statistically significant increase in mortality due to malig nant neoplasms, particularly lung cancer, among workers exposed to levels of vinyl chloride above 220 ppm. ' Duck et al" found no significant excesses in overall or cause specific mortality in a British-Petroleum chemical industry population of 2,120 male workers exposed to vinyl chloride. T tie analysis included a separate evalua tion of mortality for autoclave workers (reactor cleaners). polymer plant workers, and monomer plant workers. The authors observed no relationship between length of ex posure and risk of cancer. This particular analysis, however, has been challenged as methodologically inap propriate due to the misallocation of person-years.'1 In 1975, the National Institute for Occupational Safety and Health reported results from a follow-up study of 1,294 workers at four polymerization plants, two of which also produced vinyl chloride monomer.' All workers in cluded in the study had been exposed for five or more years with at lea:1 ten years' latency period (ten years since initial exposure). Significant risks for cancer of the liver, lung, brain and central nervous system were found for workers with 15 years-of latency. An increased risk was also observed for lymphatic and hematopoietic-* cancers. I3y contrast, the study reported by Fox and Collier" of 7,000 workers exposed to vinyl chloride in the British in dustry did not indicate that cancers other than those of the liver were associated with exposure to vinyl chloride monomer. In this study initial exposures for a fairly high proportion of the workers occurred after 1960, and follow-up by three of the eight factories was poor. In addi tion, the determination and analysis of exposure were questionable in that a measure of level of exposure ascer tained retrospectively and subjectively by the par ticipating industries was used rather than duration of ex posure, some combination of level and duration, or specific job classifications. Some background information on vinylidene chloride (VDC), a structurally similar chlorinated hydrocarbon, is _also important in this review since exposures to VDC at lower concentrations often occur simultaneously in the) VCM production area Studied. VDC is a known henatn? toxin" and has been recently described as a genetically active compound in the bacterial test systems used." " The literature contains only one report on the health and mortality experience of workers exposed to VDC without simultaneous exposure to vinyl chloride." In this study of 138 workers, Ott et al" reported no excess mortality due to malignant neoplasms or adverse health effects at tributable to exposure to vinylidene chloride. Based upon this review of the literature, the evidence associating vinyl chloride with the risk of tumors at various sites is strongly suggestive. However, some results, particularly those reported for lung cancer, are in consistent, and several questions remain regarding the strength of the association and the effects of varying levels of exposure. The present study was undertaken to further delineate the carcinogenic risk associated with ex posure to vinyl chloride by utilizing more definitive infor mation regarding duration and level of exposure, to evaluate the effects at lower doses, and to address some of the methodological problems found in other studies.'* " 10 Although it would be desirable to evaluate the specific effects of vinylidene chloride in the popula tion studied, unfortunately, it is not possible to separate its effects from those of vinyl chloride. Materials and Methods Subjects of this investigation were persons employed in a vinyl chloride monomer production plant of the Dow 196 Mortality Experience in a VCM Production Plant/Buffler et al Chemical Company. Tfce facility began operations in 1948 when a small area of the chemical [JldfU WJ!> dedicated to this operation and to_lbe simultaneous production of lirtene chloride. The criterion I6C inclusion^in the study was that an employee had worked at least two con secutive months in the vinyl chloride department be tween August 1,1948, and September 25,1975. Company personnel rosters were used to enumerate the cohort of persons who had worked in the department since 1948. Company records were utilized to compile in formation on date of birth, race, sex, and inclusive dates for each job and departmental assignment during employment. The vital status of employees who had left the company was determined by standard follow-up techniques. Death certificates were requested for all deceased employees. The certificates were coded according to the 8th Revision of the ICDA and reviewed by a nosologist provided by the Environmental Epidemiology Branch of the National Cancer Institute. Pathologic or clinical infor mation was requested from the attending physician or hospital named on the death certificate for all cancer deaths. Clinical and pathology reports received were reviewed by the UTMB Pathology Department. Personnel monitoring data at the plant since 1971 and information from the Department of Industrial Hygiene and plant supervisors allowed the grouping of all classifications with respect to potential exposure to vinyl chloride. Seven job classification groups with similar potential for exposure within each group were identified. An industrial hygienist and a panel of five persons who had long-term experience with the production process and job assignments ranked the seven categories in terms of potential for exposure to vinyl chloride during the periods 1948-70 and 1971-75. The categories were listed randomly and each member of the panel independently ranked the seven groups. The rankings were consistent from one time period to the other, suggesting that although actual levels of exposure may have changed over time, relative levels had not and the recent monitor ing data could be extrapolated backwards in time. Job classifications considered to have a relatively high potential for exposure included control lab personnel, loaders, and production personnel (control operators). A control lab worker sampled the product at several stages during the production process and analyzed it for purity. Much of this sampling is now automated. In earlier years it was common for the control lab worker to deliberately, but briefly, expose himself to vapors by methods such as the "sniff" test for sample purity, thereby incurring very high short-term exposures. Loaders are exposed to vinyl chloride in the process of connecting or disconnecting pipelines to tank cars and tank trucks. The control operators are responsible for monitoring the production process, performing minor maintenance procedures in order to insure proper functioning of equipment, and preparing equipment for major repairs. Maintenance workers generally have lower eight-hour time weighted average exposures than do the control operators, but they often experience relatively high short-term exposures to vinyl chloride while repairing worn equipment. Employees with the lowest exposures are those in super Journal of Occupational Medicine/Vol. 21, No. 3/March 1979 Table 1. -- Follow-up Status of 464 Workers in a VCM Production Plant, August 1, 1948 * September 25, 1975. Still employed at company No longer employed, alive Retired Released Deceased Died while employed Died alter leaving company Died while retired Unknown status Total ' 291 145 27 118 28 17 11 0 0 464 visory positions followed by persons in the development lab. The assignments of supervisory personnel are such that they are not required to spend extended periods of time in the production area or to be physically close to the source of vapor emissions. Development lab person nel usually work with small quantities of vinyl chloride in evaluating the product or production process. The time weighted average exposures to vinyl chloride by job classification, based upon available monitoring data, were averaged for the period 1971-75 and are summa rized in Appendix A. Standardized mortality ratios (SMR's) were computed in the analysis of the mortality experience of the cohort. Expected numbers of deaths for the study population were calculated by applying 1950-59 and 196069 agecause specific death rates for white males in Texas to the observed distribution of person-years of observation, categorized into five-year age groups. Significance testing is based on the assumption of a Poisson distribution for the observed number of deaths, utilizing a one-sided test of significance. In the analysis of the data, the effect of smoking, duration of exposure, level of exposure and the combined effect of duration and level of exposure were each considered separately, although a five-year latency requirement was maintained for all analyses except that of the effect of smoking. Results Four hundred eighty-one males were identified for in-' elusion in the study population. Evaluation of mortality risks was restricted to white males due to the small number of nonwhite males (17) in the cohort. The as certainment of vital status for the 464 white males as of the cutoff date was 100% complete, and is described in Table 1. Follow-up investigation was required for 129 in dividuals who were no longer employed Eleven of the total 28 deaths occurred among this group of 129 workers. Table 2 shows the distribution of the 28 deaths by underlying cause. Eight deaths (28.5%) were due to malig- Table 2. -- Distribution of 28 Deaths Observed Among Workers in a VCM Production Plant by Cause of Death. Causes of Death (JCDA 8th Revision) Cancer(140-209) Heart (390-458) Accident (E800-E999) Other (013 9, 330.4 and 513) All causes No. of Death 8 10 7 3 28 EC- 1522 197 Table 3. -- Case Summaries of Eight Cancer Deaths Observed Among Workers in a VCM Production Plant. Underlying Cause of Death (8th Revision ICDA) Date of Death Age at Deaths (Years) Date et Initial Exposure te VCM Age at Initial Exposure (Years) Years of VCM Exposure Interval from Date of Initial Exposure to Date Of Death (Years) Smoking pathologic History Confirmation 1. Cancer of lung (162.1) 2. Primary carcinoma lungs (162.1) 3. Carcinoma ot lung (162.1) 4. Alveolar cell carcinoma (162.1) 5. Malignant mediastinal tumor unclassified with generalized metastasis (163.1) 6. Carcinoma of colon (153.8) 7. Carcinoma of lip metas. to lung & neck (140.9) 8. Metastatic squamous cell cancer, palate (145.1) 4-21-74 12-01-58 5-21-73 11-14-71 1-28-63 4-12-71 9-03-66 9-28-71 60 . 53 68 52 21 48 31 57 11-15-48 1C 18-48 8-31-51 2-11-57 1-15-62 11-17-52 8-01-62 4-18-49 34 43 36 38 20 29 27 35 7.3 25.4 10.1 10.2 21.7 21.8 10.9 14.8 Yes Yes -- X-ray report presumptive Yes No reports available Yes No reports available Yes Yes -- Biopsy 1.0 1.0 Unk Yes -- Autopsy .6 18.4 Yes No -- Biopsy report not received * 4.1 4.1 Unk No reports available 6.0 22.4 Unk Yes -- Autopsy nant neoplasms, four of which were confirmed upon review of autopsy, biopsy or x-ray reports by the UTMB Pathology Department. Case summaries for the eight cancer deaths are shown in Table 3. No angiosarcomas or other liver tumors were observed. The eight persons who died of cancer were initially exposed to vinyl chloride prior to 1963, and lhe four with lung cancer, prior to 1958. Length of exposure to vinyl chloride ranged from seven years to 22 years in the cases of lung cancer, and the inter val from date of initial exposure to date of death ranged from 10 years to 25 years. Six of the 28 deaths reported here, including two of the eight deaths due to malignant neoplasms (malignant teratoma and alveolar cell car cinoma), occurred among a special subgroup of 165 workers exposed to 1,4-dioxane. These data were reported in an earlier mortality study of workers exposed to 1,4-dioxane" Table 4a shows the observed and expected numbers of deaths by cause. For overall mortality, the standardized mortality ratio was 11% lower than expected The total number of observed Jeaths due to malignant neoplasms was not significantly different from the expected (8 ob served vs. 5.19 expected) There is, however, a statistically significant difference between observed and expected for malignant neoplasms of the respiratory system (5 vs. 1.73, p = .03). Effect of Smoking The excess in mortality due to respiratory cancer necessitates a consideration of the effect of smoking as an explanatory variable. Differential patterns of smoking among the vinyl chloride workers as compared to the Texas white male reference population might account for this excess. The case summaries indicate that four of the five workers who died of respiratory cancer had a history of smoking; the smoking status of the fifth worker is unknown (Table 3). In addition, smoking histories are not available for a large proportion (27.6%) of the 464 white males in the total cohort. Because of the missing data on> smoking status, it is difficult to identify the ef-fecL-thaiJ smoking patterns mav nave on the results obtained. The potential effect of snicking on the expected"mortality was examined, however, by noting the consequence of an assumed pattern of smoking for the "smoking unknown" category. Assuming the availability of standard age specific rates for the two smoking categories, the ex pected mortality, under the conservative assumption that all those in the "smoking unknown" category were actual ly smokers, was computed. Unfortunately, an appropriate standard set of age specific rates according to smoking status was not readily available, but a reasonable set of rates was constructed from available information. The construction of these standard rates is described in Ap- Table 4a. -- Observed aad Expected Numbers of Deaths Among 464 White Males In a VCM Production Plant, August 1, 1948 to September 25, 1975. Cause of Death Observed Expected SMR All causes All malignant neoplasms Malignant neoplasms of the respiratory system 28 31.63 89 8 5.19 154 5 1.73 289* *p= .032, one-tailed test 198 (able 4b. -- Observed and Expected Numbers of Deaths Occurring Five or More Years Past Initial Exposure Among 314 Whita Males in a VCM Production Plant Prior to September 25, 1970. Cause o( Death All causes All malignant neoplasms Malignant neoplasms of the respiratory system Observed 22 6 4 Expected 25.18 4 34 1.49 SMR 87 138 P 268* *p = .06, one-tailed test Mortality Experience in a VCM Production Plant/Buffler et al pendix B. Under the extreme assumption that all "unknowns" actually smoked, the expected number of respiratory cancer deaths for the 464 white males is 1.98. With five deaths observed, this excess is of borderline significance (p = .05} Since it is extremely unlikely that all persons in the "unknown" category smoked, smoking appears to be an unlikely explanation for~the excess' respiratory cancer mortality. Effect of Five-Year Latency The latency period for occupationally induced cancers may range from five to 20 years from the date of first ex posure. In the above mortality comparisons, the ex periences of all workers, regardless of the length of time elapsed since initial exposure, are included. This tech nique may mask the effects of exposure in that a suffi cient latency period may not have accrued prior to death or observation. When the SMR's in Table 4a were recalculated utilizing a minimum latency period of five years from the date of initial exposure to vinyl chloride, the resulting SMR for malignant neoplasms for the 314 employees satisfying this criterion was slightly lower, 268 versus 289 (Table 4b). Effect of Duration of Exposure Fifty-four percent of the cohort had less than two years of exposure to vinyl chloride. The average length of time spent in a vinyl chloride area for all 464 workers was 4.6 years. The values ranged from a minimum of two months to a maximum of 26-9 years. It is important to determine whether increased dura tion of exposure is associated with higher mortality. When looking for such a relationship, bias may occur if the ex posure and observation periods overlap.TM Death may ter minate exposure prior to the satisfaction of some minimum exposure requirement, so that some deaths fall in the category of short duration of exposure, regardless of whether the death was causally related to the ex posure. In addition, a long duration of exposure implies a long latency period in which malignancies possibly due to other chemicals in the environment may be observed. These problems can be avoided by the following tech nique, which separates the exposure and observation periods. Duration of exposure during the first five years follow ing date of initial exposure was noted for each individual exposed prior to September 25, 1970, counting only ex posures incurred prior to that date. Individuals surviving the first five years after the date of initial exposure were then classified into two groups according to duration of exposure in the first five years. The groups were divided at the median value for duration of exposure, 2.29 years. Person-years of observation and the expected numbers of deaths for the period following the first five years since date of initial exposure were then calculated for the two groups. This procedure removes observed and expected deaths occurring among workers before completion of the minimum five-year latency period. Fig 1 illustrates the determination of these intervals for three individuals. The results of this analysis are shown in Table 5. There is a statistically significant excess of deaths due to respiratory Journal of Occupational Medicine/Vol. 21, No. 3/March 1979 cancer in the longer exposure group (4 observed vs. 1.05 expected, p = .023). Effect of Level of Exposure In order to further explore the relationship between ex posure to vinyl chloride and cancer mortality, one can consider a second dimension of exposure: the estimated level of exposure, or concentration. As previously men tioned, levels of exposure to vinyl chloride in the popula tion studied have decreased substantially in recent years, but based upon subjective evidence, tFe relative poten tial for exposure has not changed extensively. Therefore, the time weighted averages of exposures to vinyl chloride for the period 1971-75 were extrapolated backward in time to obtain an estimate of minimum exposure levels for the various job categories. Average exposure indices were obtained for each individual for the five-year period following initial exposure by multiplying the extrapolated exposure level for each job classification by the time spent in that job during the initial five-year period. These products were summed over all jobs in the initial period, then divided by the total time exposed to vinyl chloride in this initial five-year period. Only exposures before September 25,1970 were counted, thereby allowing for a five-year latency period as defined above. Categories of high and low level exposure were defined by the median extrapolated level of exposure for the 314 individuals alive and under observation at the end of the initial fiveyear period. The mortality experience observed subse quent to the initial five years for the categories of high and low average levels of exposure is illustrated in Table Exposure Storting Dote { August 1,1948 > Jonuory 1964 oevrvctioo Cut oft Dote Sept.Z5,Sept.25,! 1970 1975 I Individual B Initiol 5 yr. Observation period period Individual! A l---------- JL -X Initiol 5yc Observation period J period t it I Individual C Initiol 5 ye period exposure no exposure Fig 1. -- Example ol determination of duration of exposure during five years following date of initial exposure to vinyl chloride for three employees exposed prior to date allowing for 5-year latency (September 25, 1970). The initial date of exposure for Individual A was January 1, 1964, prior to September 25,1970 (the cutoff date minus 5 years). He died on January 1,1975. Since Individual A was continuously exposed for the entire five-year interval from the date of his initial exposure, the person-years of observation after January 1, 1969, and his death would be assigned to the long exposure category, >2.29 years. By contrast. Individual B was exposed for only two years during the five-year interval from the date of his initial exposure, contributing approximately eight person-years to the short exposure category, individual C represents an additional category of observations: those individuals for whom an initial five-year interval was not completed prior to September 25. 1970 (the study cutoff data minus 5 years) and were therefore excluded from these analyses. EC 1523 199 rr: r;i 3 Table S. -- Observed and Expected Deaths Among 314 White Males in a VCM Production Plant by Initial Five-Year Duration of Exposure.* Initial Malignant Neuiasms 5-Year AH Malignant of the Duration No. ol Person- All Causes * Neoplasms Respiratory System r (Years) Persons Years Obs. Exp. SMR Obs. Exp. SMR Obs. Exp. SMR i< Short (<_2.29) 157 1123 7 7.75 90 1 1.32 76 0 .45 0 Long (>2.29) 157 2227 15 17.43 86 5 3.02 166 4 1.05 38lt * For 314 individuals exposed before September 25.1970 and exposures incurred before that date, counting deaths occurring liva or more years after initial exposure 4 t p - .023. One failed lest 6. Again, there is a statistically significant excess of died before termination, they would have been included respiratory cancer in the group with a high average level in the study. Removing from the analysis those persons of exposure (3 deaths observed vs. .68 expected, p who terminated employment creates a tendency to 5 * = .032). overestimate the SMR, as noted in Table 8. A second potential source of bias in the analysis with limited Effect of Duration and Level of Exposure follow-up stems from the possibility that persons ter Finally, a dose-response analysis was carried out for a minating employment before retirement may differ in cer cumulative exposure index of information regarding both tain demographic or environmental characteristics duration and level of exposure. This index, for a given in related to mortality. Lastly, the elimination of a signifi - dividual and period of exposure, is the product of the cant number of individuals from the study reduces the duration of the period of exposure and the time weighted precision of the estimate of the SMR. This is particularly average level as previously defined. The mortality ex undesirable when small numbers of deaths are involved. perience occurring five years after initial exposure for in Despite these problems, it is not uncommon to find this dex groups of high and low level exposures, as defined on type of limited follow-up analysis in the literature. To 1 the basis of the first five years from initial exposure, is avoid the various sources of error in this type of analysis, .i given in Table 7. The excess in the high level exposure it is preferable to strive for a complete cohort, as was group is not statistically significant (p = .07). done in this study. Results With Limited Follow-up It is of methodologic importance to the evaluation of results from studies with incomplete follow-up, as well as to the conduct of future studies, to compare the results obtained with complete follow-up to those obtained with limited follow-up, that is, by "standard" techniques utiliz ing individuals who are easy to locate (current employees and retirees, and deaths occurring in these two groups on ly). Table 8 shows that the results with limited and with complete follow-up are similar when comparing overall mortality between the two groups, but that results differ somewhat when comparing mortality due to malignant neoplasms, specifically malignant neoplasms of the respiratory system. There are several sources of error in herent in the SMR's reported with limited follow-up. First of all, individuals removed from the analysis were certain to have survived up to their termination date. If they had Discussion One of the most challenging problems in a cohort study of the type presented here is the delineation of ex posure. Although no historical documentation of ex posure to vinyl chloride exists prior to 1970, it was reported that during the early period of production (1948-1960), exposures in the range of several hundred ppm (200-500 ppm) were not uncommon. During the 1950's and early 1960's the standard for exposure to vinyl chloride (threshold limit value, TLV) was 500 ppm.1* In 1961, based on chronic toxicity testing, the Dow Chemical Company voluntarily reduced their exposure standard to a TWA of 50 ppm (100 ppm ceiling).15 In 1974 the perma nent OSHA standard for exposure to vinyl chloride was reduced from 50 ppm to 1 ppm for an eight-hour period.14 As previously noted, workers in the cohort under study were simultaneously exposed to VCM vapors and varying Tahte 6. -- Observed and Expected Deaths Among 314 White Moles In a VCM V* ^ Production Plant by Estimated Relative Level of Exposure for .V.* Initial Five-Year Exposure Interval.* Avg. Level ot Exposure During Initial 5 Yearsf No. ot Persons PersonYears Malignant Neoplasms All Malignant of the All Causes Neoplasms Respiratory System Obs. Exp. SMR Obs. Exp. SMR Obs, Exp. SMR Low 160 1374 10 13.56 74 2 2.38 84 1 .82 122 High 154 1977 12 11.62 103 4 1.95 205 3 .68 441$ * For 314 individuals exposed before September 25. 1970, exposures incurred during the `ive-year interval horn date o! initial exposure, and counting deaths occurring five or more years after initial exposure t Based on 1971-75 monitoring data $ p=.032. cne-fo!led lest 200 Mortality Expsrience in a VCM Production Plant/Bufflor et al Table 7. -- Observed and Expected Deaths Among 314 White Males in a VCM Production Plant by Exposure Index for Initial Five-Year Exposure Intenral.* Initial 5-Year Exposure tndexf No. of Persons PersonYears Malignant Neoplasms All Malignant ef the All Causes Neoplasms Respiratory System Obs. Exp. SMR Obs. Exp. SMR Obs. Exp. SMR Low 157 1143 9 9.40 95 3 1.62 185 1 .56 180 Hiqti 157 2207 13 15.79 82 3 2.72 110 3 .94 319* * For 314 individuals exposed before September 25, 1970, exposures incurred during the five-year interval from date of initial exposure, and counting deaths occurring five or more years after initial exposure t Based on 1971-75 monitoring data X p = .07, one-tailed test concentrations of vapors from the production of VDC, ethylene dichloride, methyl chloroform and ethyl chloride. A weakness of most mortality studies of chemical indistry employees is that workers may have been exposed to many other chemicals while working in other areas of the production facility or in other chemical companies before or after the period of specific observation.VVe were able to determine that no members of the cohort had been exposed to arsenic or asbestos while they were employed at the Dow Chemical Company. In view of the lack of data regarding levels of exposure prior to 1971, an assumption was made that while levels of exposure were higher before 1971, the ratios of levels for any two job classifications remained approximately constant. It is believed that reasonable estimates of the relative levels of exposure prior to 1971 were made by backwards extrapolation of post-1971 exposure data. It is also important to note that initial exposure to vinyl chloride occurred in mid-career (34-43 years of age) for all four persons who died of lung cancer (Table 3). In this regard, the lack of information on previous employment or occupational exposures for these individuals adds to the difficulty of interpreting the significance of these statistical findings. To pursue the question of whether this excess may be causally related to VC exposure, a dose-response relation ship was examined. Dose was considered to have two dimensions, duration and level of exposure. In testing for a dose-response relationship, a.comparison of mortality may be biased if the periods of exposure and observation overlap. We avoided this source of bias by looking at an initial five-year exposure period and a subsequent obser vation period, thereby also allowing for a five-year laten cy period past initial exposure. With regard to duration of exposure in the first five years following initial exposure, there was a statistically significant excess of respiratory cancer occurring after the initial five-year period (4 versus 1.05 expected, p = .02) among workers in the longer ex posure group. No such excess was observed for workers in the shorter exposure group. In the three analyses of dose-response performed in this study, the most accurate and objective measure of dose available is duration of exposure, which ignores the concentration component of dose. On the other hand, the cumulative index takes into account both duration and level, is based on data extrapolated into the past, and assumes that the relative levels of exposure did not change over time. If this assumption were false, any ex isting dose-response relationship would be obscured, had the true cumulative indices been known. The use of the time weighted average levels as a measure of dose is not so heavily dependent on this assumption. Possible ex planations for the fact that statistical significance was observed in two of these analyses, but not the levelduration index, may be due to the potential error in the estimated levels, and in the small numbers of events observed. It should be mentioned that our inability to detect an increase in mortality in the low level exposure groups does not necessarily indicate that no increase ex ists, but may be due to the low power associated with small expected numbers, and a longer latency period at lower doses. A more appropriate statistical technique for these types of dose-response analyses might be a comparison of the increase in the high level (or long) exposure group to that in the low level (or short) exposure group. Statistical inference on the ratio of the true underlying SMR's for the two exposure groups can be carried out conditional on the number of deaths in the two groups combined.11 However, when the numbers of deaths are small, the power of such a comparison is very low, and may even be zero. Because of this inefficiency, it was deemed ap propriate not to report significance levels, but rather to note that although statistical significance was not ob served, the probability of observing such was very low. Throughout this study, as is common in occupational studies, the measure of mortality used is the SMR. There are, however, several problems with the use of SMR's that should be kept in mind when interpreting such results, especially when comparisons of SMR's are made. Limited follow-up Complete follow-up Table 8. -- Observed and Expected Deaths Among White Mates in a VCM Production Plant by Type of Follow-Up. No. of Persons PersonYears Overall Malignant Malignant Neoplasms Mortality Neoplasms of the Respiratory System Obs. Exp. SMR Obs. Exp. SMR Obs. Exp. SMR 335 3067 18 20.55 88 6 3.43 175 5 1.16 431* 464 5313 28 31.63 89 8 5.19 154 5 1.73 289f * p = .007. one-tailed test t p = .032 Journal of Occupational Medicine/Vol. 21. No. 3/March 1979 EC- 3524 201 Although the SMR is an adequate measure of excess mor tality as compared to the mortality of a standard popula tion, the comparison of two SMR's depends not only on the differences in the age specific mortality rates of each group from the standard, but also on the age specific population weightings of the two groups Thus, it is entire ly possible, if the age distributions are vastly different, that the two study groups might have equal age specific mortality rates but somewhat different SMR's. Despite the problems in the use of SMR's, no alternative was con sidered because of the small numbers involved. Conclusions In view of our inability to detect a significant dose- response relationship, we cannot state that the observed excess in respiratory cancer deaths is due to exposure to vinyl chloride. However, the fact that excesses were seen in the group with the longer duration of exposure in the initial five yea/s, and in the group with the higher average estimated exposure levels in the initial five years, suggests that a relationship may exist It is unfortunate that data were not available regarding the levels of exposure experienced 20 to 30 years ago, when the four workers with respiratory cancer were first exposed to vinyl chloride. It is also unfortunate that data were not available regarding exposures to other chemicals during these earlier decades. The results of this study can only be considered in con junction with other studies, both past and future. In view of inconsistent reports to date, more studies of the specific dose relationships and confounding exposures are needed. This study *** funded by a research award from Dow Chemical Co, U.S A The authors wish to acknowledge the support and assistance of the various Departments of Dow Chemical Co. Texas Division and USA, without whom this study could not have been conducted' the Occupational Health and Medical Research Department, the Industrial Hygiene Department, the In dustrial Medicine Department and the Personnel Department The critical review of this report by Dr Ralph Cook. Dow Chemical Co, USA and the assistance provided by the UTMB Pathology Department, the University of Texas at Houston Education and Research Computation Center, and the En vinjnmental Epidemiology Branch of the National Cancer Center in reviewing and proce$s:ng data is acknowledged This paper was issued as the Dow Technical Release B 600-48778 References 1. Monson RR and Peters JM: Proportional mortality among vinyl chloride workers. Lancet 2397-398,1974. 2. Tabershaw IR and Caffey WR; Mortality study of workers in the manufacture of vinyl chloride and its polymers. I Occup Med 16.509-513, 1974. 3. Nicholson WJ, Hammon EC, SekJman H and Selikoff IJ: Mortality' experience of a cohort of vinyl Chloride-polyvinyl chloride workers. Ann NY Acad Sci 246:225*230,1975. 4. Waxweilef R), Stringer W, Wagoner )K. and Jones ). Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 271.40-48. 1976 5. Infante P, Wagoner )K. McMichael AJ, et al- Genetic risks of vinyl chloride. Lancet 1.734-735.1976. 6. Creech JL and Johnson MN, Angiosarcoma of liver in the manufac ture of polyvinyl chloride. / Occup Med 16:150-151,1974. 7. Block J: Angiosarcoma of the liver following vinyl chloride exposure IAMA 229:53-54.1974. 8. Delorme F and Theriault G: Ten cases of angiosarcoma of the liver in Shawinigan. Quebec. I Occup Med 20:338-340,-1978. 9. Equitable Environmental Health, Inc: Epidemiologic study of vinyl chloride workers- Final report submitted to Manufacturing Chemists Association. January, 1978 202 10 Ott MC, Langnor RR, and Holder BB. Vinyl chloride exjiosurc in a controlled industrial environment Arch Environ Health 30 133-339. 1975. 11. Duck BW. Carter IT, and Coobes El: Mortality study of workers in a polyvinylchloride production plant. Lancet 2:1197-1199, 1975. 12. Wagoner JK and Infante PF. Vinyl chloride and mortality? Letters to the Editor. Lancet 2.194-195,1976. 13 Fox AJ and Collier PF: Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of potyviny! chloride in Great Britain. Br / Ind Med 34.1-10.1977. 14. Jenkins LJ, Trabulus MJ, and Murphy SD. Biochemical effects of 1,1-dichloroethyIene in rats: Comparison with carbon tetrachloride and 1, 2-diciiloroethylene. Toxicol Appl Pharmacol 23.501-510,1972. 15. McCann J, Choi E, Yamasaki E, and Ames BN: Detection of car cinogens as mutagens in the Salmonella,'microsome test Assay of 300 chemicals. Proc Natl Acad Sci 72.5135-5139.1975. 16. Bartsch H. MalaveiHe C. Montesano R. and Tomatis l; Tissue mediated mutagenicity of vinytidene chloride and2-ch!orobutadiene in S. Typhimurium. Nature 255.641-653,1975, '17. Ott MC, Fishbeck WA, Townsend MS, and Schneider EJ: A health study of employees exposed to vinytidene chloride. / Occup Med 18.735-738.1976. 18. Pasternak BS and Shore RE: Statistical methods of assessing risk following exposure to environmental carcinogens, in Environmental Health: Quantitative Methods, A. Whittemore {Ed.) Philadelphia: Society for Industrial and Applied Mathematics. 19'7, pp 49-71. 19. Liddell FDK, McDonald 1C, and Thomas DC: Methods of cohort analysis: Appraisal by application to asbestos mining. I Royal Stat Soc 140469491,1977. 20. Enterline PE. Pitfalls in epidemiological research, / Occup Med 18.150-156. 1976 21. Buffler PA. Wood SM, Suarec L. and Kilian DJ: Mortality follow-up of workers exposed to 1.4-dioxane. / Occup Med 20:255-259,1978. 22. Kahn HA: The Dorn Study of smoking and mortality among U.S. veterans: Report on eight and one-half years of observation. National Cancer Institute Monograph No. 19.1-125. U.S. Department of Health. Education, and Welfare, January 1966. 23 U.S. Department of HEW: Changes in cigarette smoking habits be tween 1955 and 1966 Public Health Serxice Publication No 1000, Series 10, No. 59, U S. Government Printing Office, Washington, D C. 24. ACGIH: Threshold limit values for I960. AMA Arch Envirn Health 1:62.1960. 25. To,kelson TR, Oyen F, and Rowe VK: The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am Ind Hyg Assoc / 22:354-361, 1961. 26. Department of Labor, Occupational Safety and Health Administra tion. Exposure of vinyl chloride, federal Register 39.35890-35898, Part II, October 4, 1974 27. Ederer F and Mantal N: Confidence limits on the ratio of two Poisson variables. Am / Epidemiol 100.165-167,1974 Appendix A Estimated Time Weighted Average (8-Hour) Exposure to Vinyl Chloride by Job Classification, 1971-1975 Percent of Total Average Person-Years Job Classification 8-Hr. TWA Exposed 1. Control lab personnel 22.3 47 2. Development lab personnel 4.1 5.7 3. Production personnel Control A 7.7 16.6 Control B 28 7.5 Control C 4.4 8.9 Class 3 operators -- .8 Total 5.7 33.8 4. Loaders and plant men Class 1, 2 operators 7.1 15.2 Head packaging operator 12.3 1.2 Material handling operator .2 .1 Mortality Experience in a VCM Production Piant/Bulller et al Packaging operator. service technician Total 5. Certain supervisory positions Production super intendent, assistant production superinten- neer, R&D engineer, engineer, safety engi neer, Sr. production engineer. Parts technician, Sr. Manager Assistant engineering technician General superintendent, section superinten dent superintendent, supervisor, assistant superintendent, plan ning engineer, material control clerk, plant assistant, head clerk, chief material handling technician, shipping coordinator, mainte nance coordinator, maintenance engineer Total Maintenar.ee personnel Boilermaker, apprentice Welder, apprentice Machinist, apprentice, helper, crew leader Pipefitter, apprentice, helper Utility man Instrument technician Production foreman, shift foreman Maintenance foreman Utility crew leader, rotating shift foreman, foreman Total -- 7.4 1.9 .2 .3 .0 1.8 '1.4 .2 1.1 1.7 .2 3.2 4.3 .4 2.5 .1 16.4 9.3 .1 .2 .0 1.9 11.6 1.2 1.1 1.7 4.2 1.2 37 5.5 .2 5.2 24.0 7. Other personnel Electrician, apprentice Loading supervisor. technical foreman. coverer, -janitor, elec trical foreman Total All groups combined 3.8 -- 3.8 5.4 2.0 1.8 3.8 100.0 For some job classifications there were no monitoring data available for the inter* val 1971*75 The value assigned was determined by averaging all monitoring data available for job classifications within the group to which the specific job classifica tion was assigned The averages computed were weighted according to total personyears in the cohort spent in each job classification. Appendix B Despite the lack of suitable standard age specific rates for smokers (present or past) and nonsmokers (never smoked), it is possible to construct a reasonable set of rates from available information. The following two simplifying assumptions are made: 1. Age specific relative risks for smokers compared to non smokers from the study by Dorn*1 for U S. white male veterans for the years 1954 to 1962, are applicable to the Texas white male populations of 1950-59 and of 1960-69. 2. The age specific percentages of smokers for U.S. males for the years 1955 and 19661* reflect the correspon ding percentages for the Texas white male population in the time periods 1950-59 and 1960-69, respectively. Using these two assumptions, a set of age specific rates for the Texas white male population according to smok ing status was constructed for use as a standard, in the following manner. Let M.= cause specific mortality rate for age group i M= cause specific mortality rate for smokers in age group i Mn= cause specific mortality rate for nonsmokers in age group i S.= proportion of population in age group i who smoke r.= age specific relative risk for smokers com pared to nonsmokers Then M. = sMb + (1 -Si) Mm = Mi[s.ri + (1 - s.)] Mm = M. / [sir. + (1-5')]; M. = mw Thus, the values for r, and s.are found for assumptions 1 and 2 above, and the desired mortality rates by smoking status are obtained. Truth Truth rests on several conditions. Among other things, truth rests on a regard for relevant facts, an intelligent assembling of them and on knowing how the facts matter. Truth also rests on knowing what is important and what is not, on judgmental capacity and on courage. -- From "When Values are Substituted for Truth'' by J Bennett, m The IVa// *trrct lovmjt, |uly 25. 1978 Journal of Occupational Medicine/Vol. 21, No. 3/March 19/9 EC- 1525 203 ^Angiosarcoma of the Spleen T< iS HQ/6 A Report of Two Cases and Review of the Literature Karl T. K. Chon, Ml); J. Crain Hollos, Ml); Knitl K. Gilbert, MU Results ot the ultrastructura! study of ore of two cases of splenic angiosarcoma established the blood vessel origin of this tumor. Fifty-three previously reported cases were reviewed. None of the 55 patients had a history ot exposure to thorium dioxide, vinyl chloride, or arsenic, which are known to be associated with hepatic angiosarcoma and other tumors. A comparison of the splenic and hepatic angiosarcomas showed that tumors not associated with exogenous material fre quently involve the spleen and liver simul taneously, and that tumors associated with thorium dioxide, vinyl chloride, or arsenic commonly involve the liver with sparing ot the spleen. (Arch Pathol Lab Med 103:122-124, 1979) Angiosarcoma of the spleen is rare. . The first case was reported by Langhans in 1879.' In 197*1, Autry and Weitzner reviewed *19 cases and added one new case." Subsequently, one case each was reported by Pollard and Millward-Sadler and Aranha eL al.' To this list, one of the four cases reported as hemangioendothelioma of the liver by Alport and Boniselr also should be added. To our knowledge no ultrastruclnral study of this splenic tumor has previously been reported. This article describes two cases of splenic angiosarcoma and presents the AmjpU'd for publication Auk 31, 14jTS. From the Department of Paiholt'Ky, Utmorsi- ty of WiM'unsin Conut for Health Sciences* Maihson, Ww. Krprim rotpiol^ to Department of D.itholoKy, Fresno Community Hospital, DO lto\ Fres no, CA !W7l.r (Dr Chen). ultrastructura! features of one of these two cases. postopcrativcly. He was alive three months after the diagnosis. REPORT OF CASES Case l.-A 31-year-old man was admit ted to the hospital because of excessive bleeding following a tooth extraction. Physical examination showed hepatomeg aly with the liver edge extending 5 cm below the right costal margin. The spleen was not felt. The hemoglobin value was 10 g/dl,. The platelet count was I I x lO'/cu mm. ami the WHO count was 10 x lO'/cu mm. The serum chemistry showed a SGOT value of SO units/L, an alkaline phospha tase concentration of If, King-Armstrong units, and a lactic dehydrogenase level of 7o0 1U/L. A liver scan showed multiple tilling defects. A laparotomy was per formed and disclosed an enlarged spleen (three times normal size) and multiple tumor nodules up to -I cm in diameter in the liver. A biopsy of the liver showed angio sarcoma. Postonoraiivolv. he was treated with supportive measures and methotrex ate. He died two months after the diagno sis. An autopsy was performed. Case 2.-A G5-year-old man was admit ted to the hospital with a two-month histo ry of left upper abdominal pain. Physical examination showed hepatosplenomcgaly; the liver extended 10 cm and the spleen 12 cm below the costal margins. His hemoglo bin level was 9.5 g/dL. The platelet count was 30 X lO'/eu mm, and the WBC count was S X 10'/cu mm. The scrum chemistry and a bone marrow examination yielded normal results. A laparotomy disclosed a massively enlarged spleen and multiple nodules up Vo 2 cm in diameter in the enlarged liver, A splenectomy and biopsy of a hepatic tumor nodule were performed. Thu patient was treated with methotrexate PATHOLOGY The autopsy in case 1 showed multi ple hemorrhagic tumor nodules up to 4 cm in diameter in the massively enlarged liver, which weighed 7,200 g (Fig 1). A single tumor nodule measuring 10 x 8 x 8 cm and weigh ing 1,000 g was found in the enlarged sjiloon. The spleen weighed 1.000 g (Fig 2). Other organs were not involved. The splenectomy specimen in case 2 weighed 1,730 g and measured 22 x 16 X 8 cm. Over 8075 of the splenie parenchyma was re placed by multiple hemorrhagic tumor nodules measuring 6 cm in the largest diameter. Microscopically, the tumor nodules in the spleens of both patients and the liver in patient 1 were composed of polygonal or oval hyperchromatic tu mor cells lining small vascular spaces that were well outlined in reticulin stains (Fig 3). Considerable amounts of hemosiderin pigments were found adjacent to the tumor tissue in the spleens of both cases. The liver biopsy in case 2 showed scattered irregular sinusoidal spaces lined by similar tumor cells (Fig 4). Extramedullary hematopoiesis was present in the neoplastic vascular spaces in the liver and spleen from case 1. There was no evidence of liver cirrhosis or tissue deposition of foreign material in ci ther case. A portion of the tumor tissue in the Fig 1.--Multiple dark reddish tumor nodules ot liver (case 1). 122 Arch Pathol Lab Med-Vol 103, March 1979 Fig 2.--Spleen containing 10-cm tumor mass (case 1). Angiosarcoma ot the Spleen--Chen et al EC- 1526